| Methods involving aldose reductase inhibitors -> Monitor Keywords |
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Methods involving aldose reductase inhibitorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Methods involving aldose reductase inhibitors description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060293265, Methods involving aldose reductase inhibitors. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional Application 60/603,725 filed on Aug. 23, 2004, U.S. patent application Ser. No. 10/462,223, filed on Jun. 13, 2004, and U.S. Provisional Application 60/388,213, filed on Jun. 13, 2003, all of which are hereby incorporated by reference. This application is a continuation-in-part of U.S. patent application Ser. No. 10/462,223, which was filed on Jun. 13, 2004. BACKGROUND OF THE INVENTION DESCRIPTION OF RELATED ART [0003] Aldose reductase (AR) catalyzes the reduction of a wide range of aldehydes (Bhatnager and Srivastava, 1992). The substrates of the enzyme range from aromatic and aliphatic aldehydes to aldoses such as glucose, galactose, and ribose. The reduction of glucose by AR is particularly significant during hyperglycemia and increased flux of glucose via AR has been etiologically linked to the development of secondary diabetic complications (Bhatnager and Srivastava, 1992; Yabe-Nishimura, 1998). However, recent studies showing that AR is an excellent catalyst for the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates (Srivastava et al., 1995; Vander Jagt et al., 1995; Srivastava et al., 1998; Srivastava et al., 1999; Dixit et al., 2000; Ramana et al., 2000) suggest that in contrast to its injurious role during diabetes, under normal glucose concentration, AR may be involved in protection against oxidative and electrophilic stress. The antioxidant role of AR is consistent with the observations that in a variety of cell types AR is upregulated by oxidants such as hydrogen peroxide (Spycher et al., 1997), lipid peroxidation-derived aldehydes (Ruef et al., 2000; Rittner et al., 1999), advanced glcosylation end products (Nakamura et al., 2000) and nitric oxide (Seo et al., 2000). The expression of the enzyme is also increased under several pathological conditions associated with increased oxidative or electrophilic stress such as iron overload (Barisani et al., 2000), alcoholic liver disease (O'Connor et al., 1999), heart failure (Yang et al., 2000), myocardial ischemia (Shinmura et al., 2000), vascular inflammation (Rittner et al., 1999) and restenosis (Ruef et al., 2000). [0004] Although glucose is a poor substrate of AR, the enzyme is recruited in renal tissues to generate sorbitol for balancing the osmotic gap during diureseis (Burg et al., 1997). The abundance and the transcription of the AR gene are dramatically enhanced by the activation of the transcription factor-TonE-binding protein (Miyakawa et al., 1999; Ko et al., 2000). However, osmotic role of AR in non-renal tissues is unclear, and the high expression of the enzyme in tissues such as heart, blood vessels, skeletal muscle or brain suggests that the enzyme may be involved in processes other than osmoregulation and glucose metabolism. Recent evidence shows that in addition to osmotic or oxidative stress, AR and its homologs are also upregulated by mitogenic stimuli. Stimulation of NIH 3T3 cells by FGF-1 (and to a lesser extent by FGF-2, EGF and phorbol esters) leads to a dramatic increase in the expression of an aldo-keto reductase-FR-1, (Donohue et al, 1994) which is related to AR in structure and function (Donohue et al., 1994; Srivastava et al., 1998). The AR protein itself is also increased by growth factors in the 3T3 fibroblasts (Hsu et al., 1997), astrocytes (Jacquin-Becker and Labourdette, 1997) and the vascular smooth muscle cells (VSMC; Ruef et al., 2000). Although the quiescent VSMC of the tunica media do not express detectable levels of AR, the expression of the enzyme is markedly induced during vascular inflammation or growth (Ruef et al., 2000; Rittner et al., 1999). Moreover, the inventors have previously shown that inhibition of AR prevents serum-induced VSMC growth in culture and neointima formation in balloon-injured rat carotid arteries (Ruef et al., 2000). [0005] Extensive investigations show that diabetes is associated with the impairment of NO-mediated vascular relaxation and a decrease in NO bioavailability, which may be a causative factor in other complications as well (Kassab et al., 2001). The second messenger NO is a diffusible gas that regulates several physiological processes, including blood pressure, platelet aggregation, and neurotransmission (van Goor et al., 2001; Torreilles, 2001; West et al., 2002). In addition, recent studies show that NO regulates glucose and oxygen consumption in the heart (Traverse et al., 2002; Recchia, 2002). However, previous studies have shown that incubation of VSMC with NO-donors results in the transcriptional upregulation of AR (Seo et al., 2000). [0006] Inhibitors of aldose reductase have been indicated for some conditions and diseases, such as diabetes complications, ischemic damage to non-cardiac tissue, Huntington's disease. See U.S. Pat. Nos. 6,696,407, 6,127,367, 6,380,200, which are all hereby incorporated by reference. In some cases, the role in which aldose reductase plays in mechanisms involved in the condition or disease are known. For example, in U.S. Pat. No. 6,696,407 indicates that an aldose reductase inhibitors increase striatal ciliary neurotrophic factor (CNTF), which has ramifications for the treatment of Huntington's Disease. In other cases, however, the way in which aldose reductase or aldose reductase inhibitors work with respect to a particular disease or condition are not known. [0007] Therefore, the role of aldose reductase in a number of diseases and conditions requires elucidation, as patients with these diseases and conditions continue to require new treatments. Thus, there is a need for preventative and therapeutic methods involving aldose reductase and aldose reductase inhibitors. SUMMARY OF THE INVENTION [0008] The present invention concerns the discovery that aldose reductase (AR) plays a direct role in certain mechanisms, which has certain ramifications for the prevention and/or treatment of conditions, disorders, and diseases that involve those mechanisms. In particular, it was found that a substance that inhibits aldose reductase can prevent or reduce the induction of chemokines and cytokines, as well as some other compounds. [0009] Thus, AR inhibitors could be used therapeutically to treat patients with sepsis, burns and other injuries such as caused by viruses and bioterrorism that have the potential of stimulating immune system and generating large amounts of inflammatory cytokines and chemokines. The AR inhibitors could also be used to prevent inflammation, mediated by cytokines and chemokines, irrespective of the source. Furthermore, patients at risk for loss of cardiac muscle contractility could be administered an AR inhibitor to reduce that risk. Moreover, AR inhibitors can be used to prevent or reduce damage to tissues or organs that occurs during the initial stages of Type I diabetes. In addition, methods can be employed to treat or prevent rheumatoid arthritis and other autoimmune diseases or conditions. [0010] The term "AR inhibitors" refers to a substance that can inhibit the activity of aldose reductase in an organism. Consequently, the substance may inhibit, prevent, preclude, and/or reduce binding activity, specificity, catalytic activity, translocation, transcription, translation, post-translational modification, transport, and/or transcript or protein stability of aldose reductase. The inhibitors may be nucleic acids, proteins (peptides or polypeptides), analogs thereof, small molecules, or any other agent or chemical that modifies the aldose reductase protein or its activity. Examples of aldose reductase inhibitors that are small molecules are well known and they include, but are not limited to, those disclosed herein. In other embodiments, the aldose reductase inhibitor is a nucleic acid, such as an siRNA, antisense molecule, or ribozyme. The inhibitor may also be a prodrug, meaning it is converted to an aldose reductase inhibitor by metabolic processes. In specific embodiments of the invention, it is contemplated that an aldose reductase inhibitor is not a nitric oxide inducer. [0011] In specific embodiments, the patient is a human patient. [0012] Therefore, in some embodiments of the invention there are methods of preventing or reducing organ or tissue damage in a Type I diabetes patient. In some embodiments, methods include: administering to a patient who has been diagnosed with Type I diabetes within 6 months an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. A patient who has only recently been diagnosed with Type I diabetes or who has only recently experienced symptoms of Type I diabetes will most likely still have a functioning pancreas and consequently not yet have experienced tissue damage caused by the diabetes. Methods of the invention can be implemented to prevent such damage, such as damage to the Isle of Langerhans. It is contemplated that a patient receives at least a first aldose reductase inhibitor within 1, 2, 3, 4, 5, 6, 7 or 8 months (or any range derivable therein) of being diagnosed with Type I diabetes or experiencing symptoms of Type I diabetes so as to prevent organ damage while the patient still has a functioning pancreas. It will be understood that in some embodiments, the patient is administered treatment during the so-called "honeymoon" phase of Type I diabetes. Moreover, it is contemplated that a patient may receive a first aldose reductase inhibitor treatment within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks of diagnosis or onset of symptom(s). In some methods of the invention, the patient is tested or evaluated for signs of a functioning pancreas. Furthermore, in additional embodiments of the invention, the patient is determined to be at risk for Type I diabetes. In some cases, the patient is tested for diabetes or is determined to be at risk based on the patient's medical history or the patient's family history. [0013] In some embodiments of the invention, there are methods of reducing the risk of loss of cardiac muscle contractility or preventing loss of cardiac muscle contractility in a patient by identifying a patient at risk for loss of cardiac muscle contractility; and/or administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. [0014] Methods of the invention also include the prevention or treatment of inflammation in a patient. Embodiments include identifying a patient with inflammation or at risk for inflammation; and/or administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. Some patients experiencing inflammation are also at risk for loss of cardiac muscle contractility. Often, such patients are either on a ventilator, experiencing a bacterial infection, and/or have been severely burned. A patient who has a bacterial infection may be a patient with pneumonia or sepsis or at least experiencing symptoms of a bacterial infection. [0015] Other methods of the invention include preventing or treating complications from sepsis in a patient comprising: a) identifying a patient with sepsis, with symptoms of sepsis, or at risk for sepsis; and/or b) administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. A patient may be identifying as having sepsis based on blood work, such as white blood cell count or an evaluation of glood gases, or a measurement of fibrinogen or on a test of urine pH. Confirmation of bacteria may be done by culturing blood or cerebrospinal fluid. Symptoms of sepsis include, but are not limited to, high fever, chills/shaking, hyperventilation, tachychardia, low blood pressure, irritability/agitation, confusion, joint pain, and hypotonia. [0016] The present invention also concerns methods of preventing or reducing lipopolysaccharide (LPS) induction of peritoneal macrophages in a patient comprising: a) identifying a patient with at risk for LPS induction of peritoneal macrophages; and/or b) administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. [0017] Methods of the invention further include treating a patient with rheumatoid arthiris (RA) and other autoimmune diseases or conditions. Methods involve administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. Such methods can be employed to treat or prevent other autoimmune diseases or conditions, which include, but are not limited to, Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmunne Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Inner Ear Disease (AIED), Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmune thrombocytopenic Purpura (ATP), Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis Herpetiformis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyclinating Polyneuropathy, Cicatricial Pemphigoid, Cold Agglutinin Disease, CREST Syndrome, Crohn's Disease, Dego's Disease, Dermatomyositis, Dermatomyositis-Juvenile, Discoid Lupus, Essential Mixed Cryoglobulinemia, Fibromyalgia Fibomyositis, Graves' Disease, Guillain Barre, Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Juvenile Arthritis, Lichen planus, Lupus, Meniere's Disease, Mixed Connective Tissue Diease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis. [0018] Also included as the invention are methods of reducing the levels of inflammatory cytokines and/or chemokines in a patient comprising: a) identifying a patient at risk for increased levels of inflammatory cytokines and/or chemokines or experiencing increased levels of inflammatory cytokines and/or chemokines; and/or b) administering to the patient an effective amount of a pharmaceutically acceptable composition comprising an aldose reductase inhibitor. Coumpounds whose levels can be reduced by an aldose reductase inhibitor in patients using methods of the invention include, but are not limited to, IL-12, IL-10, IL-6, IL-1, TNF.alpha., MCP-1, MIF, MIP1, PGE2, and/or cAMP. One, 2, 3, 4, 5, 6, 7, or more of these compounds may be elevated in a patient compared to what would be expected in a normal patient, meaning a patient not experiencing any significant symptoms of inflammation. Methods may involve determining whether the levels of one or more of these compounds is elevated either compared to normal patients not experiencing inflammation or to the same patient at a previous time. [0019] In certain embodiments, methods include a step of identifying a patient with or suspected of having a condition described herein that can be treated with an aldose reductase inhibitor. Methods may include determining the patient has a particular disease, condition, or disorder or determining the patient is at risk for a disease, condition, or disorder. They may involve subjecting the patient to one or more tests that indicate whether the patient has a disease, condition, or disorder or at least has symptoms of the disease, condition, or disorder. With Type I diabetes, a patient may exhibit signs of lethargy or appear to have sugar in his/her urine. They also can involve taking a patient interview. [0020] In other embodiments, the patient is administered the composition directly, locally, topically, orally, endoscopically, intratracheally, intratumorally, intravenously, intralesionally, intramuscularly, intraperitoneally, regionally, percutaneously, or subcutaneously. In some embodiments, compositions are administered to a patient by intravenous drip. [0021] Moreover, in some embodiments, patients are also given other therapy, such as one or more antibiotics, immunosuppressant drugs, or anti-inflammatory drugs. The other therapy may be administered before, after, or in conjunction with the composition that includes an aldose reductase inhibitor. [0022] In methods of the invention, embodiments involve administering or providing to a cell or patient an effective amount of a composition comprising an AR inhibitor. An effective amount refers to the amount that accomplishes a particular goal. In some embodiments an effective amount results in a therapeutic benefit, which is understood to encompass any therapeutic benefit to the cell or patient. Continue reading about Methods involving aldose reductase inhibitors... Full patent description for Methods involving aldose reductase inhibitors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods involving aldose reductase inhibitors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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